Safety and Efficacy Evaluation of DOTAREM® in MRI of Central Nervous System (CNS) Lesions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Evaluation of DOTAREM® in MRI of Central Nervous System (CNS) Lesions (NCT01211873), a randomized phase 3 study. The primary outcome is MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both "Pre" and "Paired" Evaluation.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, parallel-group study with quadruple masking. The registry lists enrollment of 416 participants and a completed status. The recorded study start was 2010-09, and primary completion was 2011-11. Guerbet is listed as the sponsor.

Adult participants were randomized between Dotarem and Magnevist in a 2:1 ratio. The registry separately describes pediatric participants as assigned to a Dotarem group only. Thus, the pediatric group does not have a randomized Magnevist counterpart in the description. The primary outcome analysis was restricted to adults, so the primary imaging comparison described in the record should not be interpreted as including pediatric participants.

The trial’s central imaging comparison was within the imaging evaluation: unenhanced MRI alone (PRE) versus the combination of unenhanced and Dotarem-enhanced MRI (PAIRED). The drug-arm allocation and this primary imaging comparison are related parts of the study but are not the same contrast. The registry also names image quality, diagnostic confidence, and number of lesions as secondary outcomes.

The record does not report details of the masking procedures, the randomization sequence, allocation concealment, or how the two drug groups were incorporated into each imaging analysis. It also does not report the study protocol’s statistical plan. Those details should not be inferred from the labels randomized, quadruple masking, and parallel design alone.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Any patient who did not fulfill eligibility criteria was not randomized / assigned to a treatment group.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The primary analysis was performed at the patient level using off-site readings by 3 readers. The number of participants for analysis depended on the number of evaluable cases (PRE and PAIRED) determined by each reader. Only adult participants were included in this data set.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both "Pre" and "Paired" Evaluation, measured over up to 24 hours.

The primary endpoint measures lesion visualization at the patient level. It combines three aspects: border delineation, internal morphology, and contrast enhancement. For each lesion, a three-level score runs from 0 through 1 to 2, with 0 representing a worse outcome and 2 a better outcome. A patient’s score is the sum of the scores for assessed lesions. Up to 5 of the largest representative lesions were assessed, and the possible patient-level score ranges from 0 to 10.

The endpoint compares PRE, meaning MRI before contrast administration, with PAIRED, meaning the combined unenhanced and enhanced MRI evaluations. The registry states that the analysis aimed to demonstrate superiority of PAIRED over PRE. A patient-level measure allows the evaluation to summarize the scored lesions for each person rather than treating every lesion as a separate participant. This distinction matters because a participant could contribute multiple lesion scores.

The primary analysis used off-site readings by 3 readers. The number of participants included depended on how many cases each reader considered evaluable for both PRE and PAIRED. Only adults were included in this dataset. The registry record does not report the resulting mean scores, the comparison between conditions, or uncertainty estimates. Consequently, the endpoint’s definition is available, but its observed magnitude and precision cannot be described from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is a continuous patient-level score summarized using a mean and standard deviation. The endpoint is constructed by scoring lesions, then summing the scores for each patient. The registry gives the scale’s interpretation and range, but does not report the observed means, standard deviations, or comparison estimates. The concepts below explain how such statistics are generally read; they do not supply missing study results.

What does a mean score describe?

In general, a mean is the arithmetic average of the measured scores in an analysis group. For this endpoint, the score represents the summed lesion-visualization ratings for a patient. Comparing group or condition means can describe the average level of the measured score, while the meaning of any contrast remains tied to the scale and the analysis population. A mean alone does not show how much individual scores vary, whether every participant had the same pattern, or whether the difference is estimated precisely.

What does the standard deviation describe?

In general, a standard deviation describes the spread of individual observations around their mean. It is not the same as the standard error of a mean and is not itself a measure of uncertainty about the treatment or imaging contrast. The registry identifies standard deviation as the dispersion measure for the primary outcome, but the values are not reported in the information available. Without those values and the analysis sample sizes for each reader, the observed variability cannot be characterized.

Why is the paired structure relevant?

PRE and PAIRED refer to two evaluations of imaging for the same clinical question, with PAIRED incorporating the unenhanced and enhanced MRI. In general, when two measurements come from the same participant, their relationship can matter to the analysis: a paired comparison uses within-person information, whereas an analysis treating observations as independent does not. The registry’s endpoint description names the PRE and PAIRED evaluations, but does not report the model or test used to compare them. It would therefore be inappropriate to claim a specific paired statistical procedure.

The endpoint also aggregates lesion-level ratings at patient level. In general, observations from lesions belonging to the same participant may be correlated, so treating every lesion as independent can understate uncertainty. The registry says the patient score is the sum of lesion scores and that up to 5 representative lesions were assessed. It does not report the detailed scoring rules for participants with fewer evaluable lesions, or a separate lesion-level analysis.

How should readers be considered?

Three off-site readers performed the primary analysis. The registry states that the number of participants depended on the evaluable PRE and PAIRED cases determined by each reader. This means the analysis population could vary by reader. The record does not report reader-specific sample sizes, whether reader results were combined, or whether a reader-level effect was estimated. In general, multiple readers can provide information about the consistency of image assessment, but that requires results and an analysis plan that are not reported.

What would an uncertainty interval add?

In general, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the analysis. It helps readers distinguish the estimated effect from the range of values reasonably compatible with the data and model. It does not guarantee that the true effect lies within the interval, and it does not substitute for understanding the scale or study design. No confidence interval for the primary comparison is reported in the registry record, so its precision cannot be evaluated.

A p-value, in general, describes how incompatible the observed data are with a specified null hypothesis under the analysis assumptions. It does not quantify the size or clinical importance of an effect, and it does not establish that the null hypothesis is true or false. The primary p-value is not reported. Neither a p-value nor an effect estimate can be reconstructed from the endpoint definition alone.

What do the planning illustrations mean?

The registry’s sample-size assumptions describe planning illustrations based on an observed effect, not the trial’s own design calculation. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. These assumptions describe an illustrative calculation framework, not the actual adult 2:1 allocation or the pediatric group structure. No calculated sample-size values are included in the registry record for this explanation. Such illustrations are planning quantities and are not observed power. The registry record does not report the original sample-size justification or whether these were the assumptions used to design the trial.

More generally, power is a property of a specified design, target effect, variability, sample size, and statistical procedure. It should not be calculated after the study by substituting the observed effect and then presented as evidence that a result is reliable. In this case, the primary estimates and variability are not reported, so the planning illustration cannot be independently interpreted as a trial result.

10. Multiplicity, Missing Data and Analysis Populations

The registry records 4 outcome measures and 5 analyses. It identifies the primary lesion-visualization outcome and lists image quality score, diagnostic confidence score, and number of lesions as secondary outcomes. The primary endpoint itself includes three visualization components and compares PRE with PAIRED. The record also describes readings by 3 readers. These features create multiple possible results to report, but the registry information does not establish how the analyses were prioritized or whether any adjustment for multiple comparisons was planned or applied.

The record indicates that the primary outcome has several categories or time points and is not reduced to one comparison. It therefore does not present a single consolidated primary comparison in the information available for this analysis. No multiplicity procedure, hierarchical testing strategy, or prespecified rule for interpreting the several components and reader results is reported in the registry record. Statistical significance across multiple tests can be harder to interpret when the testing strategy is unknown; this is a general consideration, not a finding about this trial.

The primary analysis population was limited to adults and depended on evaluability for both PRE and PAIRED as determined by each reader. Reader-specific participant counts and the reasons for non-evaluability are not reported. The registry does not describe how missing outcome data were handled, whether any imputation was used, or whether analyses were restricted to complete cases beyond the stated evaluability requirement. It also does not report a sensitivity analysis for missing or unevaluable observations.

Adults were randomized between Dotarem and Magnevist in a 2:1 ratio, while pediatric participants were assigned to the Dotarem group only. This distinction is important when considering which comparisons are randomized and which populations contribute to the primary endpoint. The primary outcome description explicitly excludes pediatric participants. Further details about analysis populations, exclusions, protocol deviations, and the handling of randomized participants are not reported in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypoxia (2.6%), neurological decompensation (2.6%), small intestine perforation (0.9%).

The registry records serious adverse events for three groups: Dotarem adult participants, Magnevist adult participants, and pediatric participants assigned to Dotarem. The serious-event figures are 0 of 240, 1 of 117, and 1 of 38, respectively. No deaths are recorded in any of these groups. These are counts of affected participants and participants at risk as recorded; they should be read as descriptive group summaries.

The registry lists hypoxia at 2.6%, neurological decompensation at 2.6%, and small intestine perforation at 0.9% among the top serious terms. It does not specify an arm-level attribution for those percentages in the information used for this description. They should not be assigned to a particular group without that information. The record also lists other adverse events affecting 12 of 240 adult Dotarem participants, 9 of 117 adult Magnevist participants, and 8 of 38 pediatric Dotarem participants.

In general, event counts depend on the participants observed, the event definitions, and the period and method of surveillance. A count of zero does not establish that an event cannot occur, and raw counts do not by themselves show whether groups differ. The registry record does not report the event-collection timeframe, exposure-adjusted rates, formal comparative safety estimates, or confidence intervals. The safety figures therefore describe what was recorded in these groups, rather than establishing a comparative safety conclusion.

12. What the Result Does, and Does Not, Mean

The study asks a defined imaging question: whether combining unenhanced MRI with Dotarem-enhanced MRI improves the patient-level lesion-visualization score compared with unenhanced MRI alone. The scoring scale has an explicit direction, and the record explains how lesion ratings contribute to each patient’s score. These details make the intended measurement interpretable in principle.

However, the primary outcome estimates are not reported in the registry record. There is no reported PRE mean, PAIRED mean, contrast estimate, confidence interval, or primary p-value in the information described. The stated superiority objective cannot be taken as proof that superiority was demonstrated. Without the results, the magnitude and precision of any difference remain unknown.

Even if a score contrast were available, it would describe this defined imaging score in the analyzed population. It would not automatically answer every question about diagnostic accuracy, clinical decisions, patient outcomes, or performance in populations not represented by the analysis. The record’s primary analysis includes adults only and relies on cases deemed evaluable by each reader. Pediatric participants were assigned to Dotarem only and do not form part of the primary analysis dataset described.

The safety counts are also limited in scope. They record serious adverse events and other adverse events in the stated groups, but do not provide a complete account of event timing, exposure, or comparative uncertainty. The counts do not establish that an event is impossible when no case was recorded, nor do they demonstrate a difference between groups.

Thus, the registry supports a clear description of the study design, endpoint, and selected safety observations. It does not support a quantitative conclusion about the primary imaging comparison. Interpretation should separate the question the study intended to answer from the estimates and inferential results that would be needed to answer it.

13. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is not simply a comparison of two randomized drug groups. The main endpoint contrasts unenhanced MRI with a combined evaluation that includes Dotarem-enhanced MRI, while adult participants were also randomized between Dotarem and Magnevist in a 2:1 ratio. Keeping the imaging contrast distinct from the drug allocation prevents a mistaken interpretation of what the primary endpoint is designed to compare.

The patient-level score also illustrates how the unit of analysis shapes interpretation. Multiple lesions could contribute to one patient’s sum, and each participant could have up to 5 representative lesions assessed. The analysis therefore summarizes lesion ratings within a patient rather than treating each lesion as an independent participant. The record’s use of off-site readings by 3 readers adds another source of measurement variation, and the number analyzed could depend on each reader’s evaluation of paired cases.

These design details matter because an endpoint can be clearly defined while its results remain unavailable. The scale, scoring direction, and intended comparison explain what a result would mean, but they cannot substitute for the means, contrasts, uncertainty intervals, and testing results. The registry record does not report those primary estimates, limiting statistical interpretation despite the detailed endpoint description.

The adult and pediatric allocation patterns also make population boundaries important. The primary dataset includes adults only, whereas the pediatric group was assigned to Dotarem alone. A pooled interpretation would not be justified from the information recorded. Overall, the study highlights why readers need to distinguish endpoint construction, analysis population, randomized allocation, and reported effect estimates when interpreting a clinical trial.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for statistical interpretation is the absence of reported primary outcome results. The registry defines the lesion-visualization score and the intended PRE-versus-PAIRED comparison, but does not report the mean scores, effect estimate, confidence interval, or p-value. The primary objective therefore cannot be evaluated quantitatively from the registry record.

The record says that evaluability was determined separately by each of 3 readers and that the number of participants analyzed depended on evaluable PRE and PAIRED cases. Reader-specific analysis counts, reasons for unevaluable data, and methods for combining reader results are not reported. Missing-data handling and sensitivity analyses are also not reported, so the influence of incomplete or non-evaluable assessments cannot be assessed.

The endpoint sums scores for up to 5 representative lesions, but further details on how incomplete lesion assessments were handled are not reported. The record also does not give the statistical model or test used for the primary comparison. Although it records 4 outcome measures and 5 analyses, it does not describe multiplicity control or a hierarchy for interpreting the multiple components and reader analyses.

The primary analysis is restricted to adults, while pediatric participants were assigned to Dotarem only. This limits the scope of the primary comparison as described and does not provide a randomized pediatric drug comparison. The registry’s safety counts are not accompanied by event follow-up duration, exposure-adjusted rates, or comparative uncertainty estimates. Finally, the original sample-size justification and full statistical plan are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy Evaluation of DOTAREM® in MRI of Central Nervous System (CNS) Lesions — NCT01211873.
• Registry record last updated 2019-04-18; status last verified 2019-04.
• Results first posted 2014-05-29.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes a completed Phase 3 randomized, parallel-group study with quadruple masking and enrollment of 416 participants. Adults were randomized between Dotarem and Magnevist in a 2:1 ratio; pediatric participants were assigned to Dotarem only. The primary analysis included adults and compared unenhanced MRI with combined unenhanced and Dotarem-enhanced MRI for patient-level lesion visualization.

The endpoint sums lesion scores on a scale with patient-level values from 0 to 10, using off-site readings by 3 readers. The number analyzed depended on reader-specific evaluability. The registry record does not report the primary outcome estimates or inferential results. It records serious adverse events in the three groups and no deaths, but does not provide the detail needed for a comparative safety conclusion. The statistical interpretation is therefore limited by missing primary results and unreported analysis details.